Hypoimmunogenic Biotherapeutics

Abstract

The present disclosure provides hypoimmunogenic biotherapeutic compositions that suppress the development of an immune response to themselves in an individual. The present disclosure also provides pharmaceutical compositions that include such hypoimmunogenic biotherapeutics, methods for making such hypoimmunogenic biotherapeutics, and methods for using such hypoimmunogenic biotherapeutics as therapeutics and in research.

1 .- 104 . (canceled) 
     
     
         105 . An engineered hypoimmunogenic biotherapeutic, comprising a biotherapeutic which has been engineered to comprise an elevated amount of Sialic acid-binding immunoglobulin-type lectin (Siglec) ligand relative to a corresponding unengineered biotherapeutic while retaining therapeutic activity. 
     
     
         106 . The engineered hypoimmunogenic biotherapeutic of  claim 105 , wherein the engineered hypoimmunogenic biotherapeutic is of formula (I):
   [X n -L] m -Y   (I)
   wherein X is a sialic acid group, L is a linker, Y is a biotherapeutic, n is an integer of 1 or more, and m is an integer of 2 or more.   
     
     
         107 . The engineered hypoimmunogenic biotherapeutic of  claim 106 , wherein in is an integer of 3 or more. 
     
     
         108 . The engineered hypoimmunogenic biotherapeutic of  claim 105 , wherein the Siglec ligand comprises a linker that does not include a saccharide. 
     
     
         109 . The engineered hypoimmunogenic biotherapeutic of  claim 105 , wherein the Siglec ligand comprises a sialic acid and a linker and wherein the Siglec ligand does not comprise a saccharide between the linker and the sialic acid. 
     
     
         110 . The engineered hypoimmunogenic biotherapeutic of  claim 106 , wherein L comprises a polyethylene glycol group. 
     
     
         111 . The engineered hypoimmunogenic biotherapeutic of  claim 106 , wherein L is a branched linker comprising one or more branching groups. 
     
     
         112 . The engineered hypoimmunogenic biotherapeutic of  claim 105 , comprising one or more Siglec ligands covalently bound to the biotherapeutic, wherein the one or more Siglec ligands comprise: 
       
         
           
           
               
               
           
         
       
     
     
         113 . The engineered hypoimmunogenic biotherapeutic of  claim 112 , wherein the Siglec ligand comprises a linker comprising: 
       
         
           
           
               
               
           
         
         wherein the linker attaches the sialic acid to the biotherapeutic. 
       
     
     
         114 . The engineered hypoimmunogenic biotherapeutic of  claim 105 , wherein the Siglec ligand comprises: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         115 . The engineered hypoimmunogenic, biotherapeutic f  claim 105 , wherein the biotherapeutic is a protein. 
     
     
         116 . The engineered hypoimmunogenic biotherapeutic of  claim 115 , wherein the protein is an antibody, an enzyme, a chimeric protein, or a viral particle. 
     
     
         117 . The engineered hypoimmunogenic biotherapeutic of  claim 116 , wherein the protein is an antibody and wherein the antibody adalimumab, infliximab, cetuximab, natalizumab, moxetumomab pasudotox, atezolizumab, nivolumab, abciximab, Brentuximab, Certolizumab pegol, elotuzumab, benralizumab, vedolizumab, galcanezumab, rituximab, alemtuzumab, dupilumab, golimumab, obinutuzumab, tildrakizumab, erenumab, mepolizumab, tamucirumab, ranibizumab, ustekinumab, reslizumab, ipilimumab, alirocumab, belimumab, panitumumab, avelumab, necitumumab, mogamulizumab, olaratumab, brodalumab, eculizumab, pertuzumab, pembrolizumab, or tocilizumab. 
     
     
         118 . The engineered hypoimmunogenic biotherapeutic of  claim 116 , wherein the protein is an enzyme and wherein the enzyme is IdeS, asparaginase  Erwinia chrysanthemi , phenylalanine ammonia-lyase, alpha-galactosidase A, acid α-glucosidase (GAA), glucocerebrosidase (GCase), aspartylglucosaminidase (AGA), alpha-L-iduronidase, iduronate sulfatase, sulfaminase, α-N-acetylglucosaminidase (NAGLU), heparin acetyle CoA: α-glucosaminide N-acetyltransferase (HGSNAT), N-acetylglucosamine 6-sulfatase (GNS), N-glucosamine 3-O-sulfatase (arylsulfatase G or ARSG), N-acetylgalactosamine 6-sulfatase, beta-galactosidase, N-acetylgalactosamine 4-sulfatase, beta-glucuronidase, Factor VIII, Factor IX, palmitoyl protein thioesterase (PPT1), Tripeptidyl peptidase (TPP1),  Pseudomonas  elastase (PaE),  Pseudomonas  alkaline protease (PaAP), or Streptococcal pyrogenic exotoxin B (SpeB). 
     
     
         119 . A pharmaceutical composition, comprising:
 the engineered hypoimmunogenic biotherapeutic of  claim 105 ; and   a pharmaceutical excipient.   
     
     
         120 . A method of treating an individual suffering from a disorder or disease treatable by administration of a biotherapeutic agent, the method comprising administering to the individual the pharmaceutical composition according to  claim 119  in an amount effective to treat the disorder or disease, wherein the pharmaceutical composition elicits a reduced anti-drug antibody titer relative to the unengineered biotherapeutic. 
     
     
         121 . The method of  claim 120 , wherein the disease is a chronic immune disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis, wherein the administering comprises administering to the individual an engineered hypoimmunogenic TNFα-specific antibody selected from adalimumab and infliximab in an amount effective to treat the chronic immune disease. 
     
     
         122 . The method of  claim 120 , wherein the disease is leukemia, wherein the administering comprises administering to the individual an engineered hypoimmunogenic asparaginase from  Erwinia chrysanthemi  in an amount effective to treat the cancer. 
     
     
         123 . The method of  claim 120 , wherein the disease is multiple sclerosis, wherein the administering comprises administering to the individual an engineered hypoimmunogenic natalizumab, an engineered hypoimmunogenic IFNβ-1b, or an engineered hypoimmunogenic IFNβ-1a in an amount effective to treat the multiple sclerosis. 
     
     
         124 . The method of  claim 120 , wherein the disorder is an antibody response to a transplanted tissue, wherein the administering comprises administering to the individual an engineered hypoimmunogenic IdeS in an amount effective to suppress the antibody response to the transplanted tissue. 
     
     
         125 . The method of  claim 120 , wherein the disorder is Type 2 Diabetes, wherein the administering comprises administering to the individual an engineered hypoimmunogenic exenatide or engineered hypoimmunogenic albiglutide in an amount effective to treat the disorder. 
     
     
         126 . The method of  claim 120 , wherein the disorder is an enzyme deficiency, wherein the administering comprises administering to the individual an engineered hypoimmunogenic enzyme in an amount effective to treat the deficiency. 
     
     
         127 . The method of  claim 126 , wherein the enzyme deficiency is a deficiency for an enzyme selected from the group consisting of phenylalanine ammonia-lyase (PKU), alpha-galactosidase A (for Fabry), acid α-glucosidase (GAA, for Pompe), glucocerebrosidase (GCase, for Gaucher), aspartylglucosaminidase (AGA, for Aspartylglucosaminuria), alpha-L-iduronidase (for MPS I), iduronate sulfatase (for MPS II), sulfaminase (MPS IIIa), α-N-acetylglucosaminidase (NAGLU, for MPS IIIB), heparin acetyle CoA: α-glucosaminide N-acetyltransferase (HGSNAT, for MPS IIIC), N-acetylglucosamine 6-sulfatase (GNS, for MPS IIID), N-glucosamine 3-O-sulfatase (arylsulfatase G or ARSG, MPS IIIE), N-acetylgalactosamine 6-sulfatase (for MPS IVA), beta-galactosidase (for MPS IVB), N-acetylgalactosamine 4-sulfatase (for MPS VI), beta-glucuronidase (for MPS VI), Factor VIII (for hemophilia A), Factor IX (for hemophilia B), palmitoyl protein thioesterase (PPT1, for CLN1), Tripeptidyl peptidase (TPP1, for CLN2), and cystathionine beta synthase (CBS) deficiency. 
     
     
         128 . The method of  claim 120 , wherein the disorder is a monogenic disease, wherein the administering comprises administering to the individual an engineered hypoimmunogenic viral particle comprising a transgene encoding a therapeutic product in an amount effective to treat the disease.